Background The coronavirus disease 2019 (COVID-19) can severely affect people with comorbidities such as those with diabetes, hypertension, chronic lung disease, cancer, and hemoglobinopathies. Studies assessing the clinical characteristics and immune response to COVID-19 infection in patients with thalassemia are limited. Objectives The primary objective of the study was to study the clinical pattern and the immunoglobulin G (IgG) antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with transfusion-dependent thalassemia (TDT) compared to patients without thalassemia. The secondary objective wasto study the relationship of COVID-19 severity with IgG antibody titers. Setting, Design, and Participants This case-control study was conducted at a tertiary care hospital between January 2021 and August 2022. A total of 30 patients with TDT (mean age: 12.7 years, SD: 4.7) and 30 patients without thalassemia (mean age: 13.9years, SD: 7) who tested positive for COVID-19 in the preceding six weeks were recruited. Methods Serum samples from the cases and controls were collected after 6, 12, and 24 weeks of COVID-19 infection for IgG antibody estimation using chemiluminescent immunoassay. Outcome variables The primary variable was comparative analysis of antibody levels and clinical profile of COVID-19 in cases and controls. The secondaryvariable was association of the severity of COVID-19 with the antibody titers produced. Results Symptomatic individuals among cases (n=12) were significantly lesser than controls (n=22) (p=0.009). The median IgG titers of cases and controls were comparable at six weeks (p=0.40), but the titers were significantly lower for cases at 12 weeks (p=0.011) and 24 weeks (p=0.006). There was significant fall in titers from 6 to 12 and 24 weeks in both the groups. The titers were not affected by COVID-19 severity and pre-existing comorbidities. Conclusion Patients with TDT manifest with mild or asymptomatic COVID-19 and mount a comparable IgG antibody response to COVID-19 akin to controls. However, this serological response could not sustain over three to six months advocating the need for protection through vaccination.